The importance of dopamine in CNS activity is well recognized, and dopamine receptors have been important targets for drug development. O. Civelli et al., “Molecular Diversity of the Dopamine Receptors”, ANNU. REV. PHARMACOL. TOXICOL. 32, 281–307, 1993; P. Seeman et al., “Dopamine Receptor Pharmacology”, TIPS, 15, 264–270, 1994. Detailed investigation has recently revealed the existence of several subtypes of dopamine (“DA”) receptors. See Civelli, op. cit., Seeman, op. cit., and J. W. Kebabian et al., “Multiple Receptors for Dopamine”, NATURE, 277, 93–96, 1979. From cloning of DA receptor forms and isoforms, two main D1-like (D1 and D5) and D2-like (D2, D3, and D4) categories of DA receptors can be identified. Civelli, op. cit., Seeman, op. cit.
Of the receptor subtypes, the D3 receptor is distributed in the limbic area of the human brain, but absent from the caudate and putamen. This distribution makes the D3 receptor a potential target for drugs with an unusual spectrum of activities, in particular, CNS activities focused on specific disorders. For example, D3 antagonists may exhibit activity as atypical antipsychotic agents. D3 agonists have potential application in the therapeutic treatment for Parkinson's disease. B. Giros et al., ACAD. SCI [III] 1990, 311, 501. Recent studies suggest that D3 specific compounds may be useful in treating cocaine addition. S. G. Caine et al., “Modulation of Cocaine Self-administration in the Rat through D-3 Dopamine Receptors”, SCIENCE, 260, 1914–1816, 1993; S. B. Caine et al., “Pretreatment With The Dopamine Agonist 7-OH-DPAT Shifts the Cocaine Self-administration Dose Effect Function to the Left Under Different Schedules in the Rat”, BEHAV. PHARMACOL. 6, 33–347, 1995; D. B. Calne et al., “Therapeutics and Neurology”, BLACKWELL SCIENTIFIC PUBLICATIONS, Oxford, 1980.
Several CNS drugs and drug candidates have been developed which exhibit selectivity for the D1 or D2 families of DA receptors. Some of these compounds have been shown to also exhibit limited selectivity for DA receptor subtypes. For example, clozapine, an atypical psychotic agent, exhibits preferential antagonist activity for the D4 receptor, and is now used in treating schizophrenia. H. H. M. Van Tol et al., “Cloning of the Gene for a Human Dopamine D4 Receptor with High Affinity for the Antipsychotic Clozapine”. NATURE, 350, 610–614, 1991. Several D2 agonists, for example 7(+)-OH-DPAT,
(+)PD 128907
and quinpirole
have recently been shown to have preferential affinity for the D3 receptor. D. Levesque et al., “Identification, Characterization, and Localization of the Dopamine D3 Receptor in Rat Brain Using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. PROC. NATL. ACAD. SCI. U.S.A. 89, 8155–8159, 1992; T. A. Pugsley et al., “Neurochemical and Functional Characterization of the Preferentially Selective Dopamine D3 Agonist PD 128907, PHARMACOL. EXP. THER. 275, 1355–1366, 1995; R. G. MacKenzie et al., “Characterization of the Human Doparnine D3 Receptor Expressed in Transfected Cell Lines”. EUR. J. PHARMACOL., 266, 79–85, 1994. The ability to exhibit differential activity with respect to different DA receptor subtypes can significantly alter treatment possibilities. In addition to the expected consequence of achieving unique CNS response due to the stimulation of but one receptor subtype rather than several, it is also conceivable that differential dopaminergenic drugs having differential effects might be used in “push-pull” fashion, i.e., one drug which is an antagonist for the D3 receptor in combination with an agonist or antagonist for another receptor, but which does not affect the D3 receptor. Such strategies cannot be used when drug candidates do not display differential activity.
Much progress has been made in dopaminergenic response at the D3 receptor since its cloning in 1990. P. Sokoloff et al., “Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics”, NATURE, 347, 146, 1990. Several specific compounds have been identified which are relatively selective for the D3 receptor. The majority of these compounds belong to the class of 2-aminotetralins. J. G. Canon et al., “Centrally acting Emetics. 6. Derivatives of β-Naphthylamine and 2-Indanamine”, J. MED. CHEM. 15, 348–350, 1972; J. G. Canon et al., “Cerebral Dopamine Agonist Properties of Some 2-Aminotetralin Derivatives after Peripheral and Intracerebral Administration”, J. MED. CHEM. 20, 1111–1116, 1977; J. McDermed et al., “Synthesis and Pharmacology of Some 2-Aminotetralins. Dopaminae Receptor Agonists”, J. MED. CHEM., 18, 362–367, 1975; J. D. McDermed et al., “Synthesis and Dopaminergic Activity of (±)-, (+)-, and (−)-2-Dipropylamino-5-hydroxy-1,2,3,4-tetrahydronaphthalene”, J. MED. CHEM. 19, 547–549, 1976; U. Hacksell et al., “N-alkylated 2-Aminotetralins: Central Dopamine-Receptor Stimulating Activity”, J. MED. CHEM. 22, 1469–1475, 1979. Further studies have investigated large numbers of 5-hydroxy-2-amninotetralin derivatives, and systematic screening has identified several drug candidates with at least some D3 selectivity. L. Alexander Van Vliet et al., “Affinity for Dopamine D2, D3 and D4 Receptors of 2-Aminotetralins. Relevance of D2 Agonist Binding for Determination of Receptor Subtype Selectivity”, J. MED. CHEM. 39, 4233–4237, 996.
SAR studies have shown that both 7-hydroxy and 5-hydroxy derivatives of 2-aminotetralin are active at the D2L and D3 receptors, with 7-hydroxy-2-aminotetralins exhibiting preferential affinity for the D3 receptor as compared to their 5-hydroxy analogous. Further, while both 5-hydroxy- and 7-hydroxy-2-aminotetralins exhibited dopaminergenic behavior, 8-hydroxy analogs produced serotoninergic activity. Binding assays also make clear that different optical isomers display different activities. J. D. M. McDermed et al., op. cit.
In the class of hydroxy-substituted-2-aminotetralins, it has been believed that at least one n-propyl group is necessary as an amino group substituent to confer significant receptor activity. The nature of the second amino nitrogen substituent is apparently less important based on these studies, although some studies have shown that bulky alkylaromatic substituents increase activity. The importance of at least one N-(n-propyl) group and preferably two n-propyl groups can be shown by R(+)-7-OH-DPAT, Pramipexole, (+)-PD 128907, and (+)-S-14297, which have structures I through IV, respectively:
All these compounds possess two N-(n-propyl) groups or, in the case of III, a closely related structure. All exhibit some preference for the D3 receptor. However, their differential binding capacity is limited, and appears to vary with the nature of the receptor binding state. For example, I was found to be about 100 times more selective for the D3 receptor as compared to the D2 receptor when displacing [3H]spiperone under experimental conditions which favored a low affinity D2 state. However, I was only 60 times more selective when the high affinity states of D2 and D3 receptors were compared. Based both on these studies and on behavioral studies, it is believed that in vivo, I binds to the D3 receptor at low concentration, but at higher concentration becomes non-selective. M. S. Starr et al., “Motor Actions of 7-OH-DPAT in Normal and Reserpine-Treated Mice Suggest Involvement of Both Dopamine D2 and D3 Receptors”. EUR. J. PHARMACOL. 277, 151–158, 1995. Thus, for drug candidates which exhibit behavior similar to I, unless the compound exhibits high activity at very low concentration, the desired selectivity between receptors will be lost when the concentration is increased to pharmacogically useful levels.
Compound III and Nafadotride, the latter not related chemically to aminotetralins, have recently been shown to be among the most potent D3 antagonists. Although these compounds show some preference for binding to the D3 receptor, they still exhibit a high affinity to the D2 receptor as well.
In Lin et al. U.S. Pat. No. 5,545,755, an enormously large number of 2-aminotetralins are disclosed which may have either serotoninergenic or dopaminergenic activity. However, only selectivity between the 5-HT1A (5-hydroxytryptamine) receptor and dopamine D2 receptor is disclosed; no selectivity between seratonin and dopamine receptors or between dopamine subtype receptors is reported.
It is well known in the pharmaceutical industry that drug pharmacology can vary considerably between different patients. A drug candidate which is highly effective in one patient may be ineffective in others. In some cases, drug allergies or unintended and unwanted side effects may mitigate against prescribing a drug to certain individuals. Thus, it would be desirable to provide additional dopaminergenic and serotoninergenic drug candidates of high activity which are different chemically and/or pharmacologically from those developed previously. It would also be desirable to provide drug candidates which exhibit differential binding activities, especially between dopamine receptor subtypes. It would be yet further desirable to provide drug candidates in which the selectivity between receptors is higher than presently available.